CN107235994B - Simultaneously [3,2-a] pyrimidine -3- acetamide derivative and the application of 5,7- diphenyl -5H- thiazole - Google Patents
Simultaneously [3,2-a] pyrimidine -3- acetamide derivative and the application of 5,7- diphenyl -5H- thiazole Download PDFInfo
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- CN107235994B CN107235994B CN201710703904.4A CN201710703904A CN107235994B CN 107235994 B CN107235994 B CN 107235994B CN 201710703904 A CN201710703904 A CN 201710703904A CN 107235994 B CN107235994 B CN 107235994B
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- pyrimidine
- thiazole
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
Abstract
The invention discloses 5,7- diphenyl -5H- thiazole simultaneously [3,2-a] pyrimidine -3- acetamide derivative or its pharmaceutically acceptable hydrates, salt, including its stereoisomer or tautomer of general formula I, wherein the R in Formulas I1And R2It is independently hydrogen, methyl, halogen, hydroxyl, methoxyl group, acetyl group, propiono, nitro or alkoxy；R3And R4Independent alkyl or R selected from C1-C63And R4Pyrrole radicals is formed together with the nitrogen-atoms being connected with them, piperidyl, morpholinyl, N methyl piperazine, N- (4- bromophenyl piperazine) it is of the invention 5, simultaneously [3,2-a] pyrimidine -3- acetamide derivative is as vascular endothelial growth factor receptor tyrosine kinase inhibitor for 7- diphenyl -5H- thiazole, for treating and preventing the purposes of various cancers.
Description
Technical field
The invention belongs to pharmaceutical technology field more particularly to 5,7- diphenyl -5H- thiazole simultaneously [3,2-a] pyrimidine -3- acetyl
Amine derivant and preparation method thereof with as -2 tyrosine kinase inhibitor of vascular endothelial growth factor receptor, for treating and
The purposes for preventing various cancers.
Background technique
Malignant tumour is one of the principal disease that today's society threatens human health, and 1971, Folkman proposed tumour
Generation, development are closely related with angiogenesis.The growth of tumour and transfer are dependent on oxygen provided by angiogenesis and necessary
Nutriment.Entity tumor there is no angiogenesis at the beginning of being formed, and the nutrition of tumour cell is mainly obtained by disperse, when cell away from
When from 200 μm of capillary or more, nutrition will be unable to arrive at tumour cell by dispersion, when the cell number of tumour reaches 1
×107After a, the nutrition that disperse obtains has been unable to satisfy the needs of tumor survival and growth, at this time as raw without new blood vessel again
At tumor tissues will degenerate.Over more than 30 years, a large amount of clinical practice and experimental study are confirmed: angiogenesis is that tumour is raw
Long and transfer prerequisite and all malignant tumours general character, the angiogenesis for inhibiting tumour to mediate can effectively press down
The growth and transfer of tumour processed.
Angiogenesis be one by it is numerous adjust, regulatory factor adjust complex physiologic, pathologic process, at present it is separated and
It has been purified into more than 20 kinds of angiogenesis factors and correlation factor, at least 15 kinds of angiogenesis inhibitors.Its Endothelial Cell
Growth factor (vascular endothet ial growth factor, VEGF) is in core status, is to be currently known activity
Most strong, the highest angiogenesis factor of specificity.Vascular endothelial growth factor receptor (Vascular Endothelial
Growth Gactor Receptor, VEGFR) be VEGF specificity membrane receptor, have high-affinity.Currently, consistent
View is the main agencies factor that sexually revises of mitogenesis, Angiogensis and infiltration that VEGFR-2 is VEGF.In addition,
VEGFR-2 is almost only specifically expressed on endothelial cell, and endothelial cell membrane is not easy to be mutated because stable, passes through inhibition
VEGFR-2 can it is exclusive, effectively inhibit tumour cell angiogenesis, and be not likely to produce drug resistance.Therefore, using new vessels as target
Point is treated the research hotspot also become in recent years to tumour.
Summary of the invention
The purpose of the present invention is to provide a kind of 5,7- diphenyl -5H- thiazole, simultaneously [3,2-a] pyrimidine -3- ethanamide spreads out
Biology, with good anti-tumor activity.
Above-mentioned purpose of the invention is achieved by the following technical solution:
A kind of VEGFR-2 tyrosine kinase inhibitor, have anti-tumor activity, it is characterised in that: the compound be with
Simultaneously [3,2-a] pyrimidine -3- acetamide derivative or its pharmaceutically acceptable hydration of the 5,7- diphenyl -5H- thiazole of general formula I
Object, salt, including its stereoisomer or tautomer；
Wherein, the R in Formulas I1And R2Independently be hydrogen, methyl, halogen, hydroxyl, methoxyl group, acetyl group, propiono,
Nitro or alkoxy；R3And R4Independent alkyl or R selected from C1-C63And R4Pyrrole is formed together with the nitrogen-atoms being connected with them
Cough up base, piperidyl, morpholinyl, N methyl piperazine, N-(4- bromophenyl piperazine).
The term " halogen " applied in the present invention includes fluorine, chlorine or bromine.
The present invention also provides the purposes that above compound is used to prepare anti-tumor drug.
" pharmaceutically acceptable salt " refers to the biopotency and property for remaining type I compound, and with suitable non-toxic
The conventional acid addition salts or base addition salts that organic or inorganic acid or organic or inorganic alkali are formed.The example of acid-addition salts includes acetic acid
Salt, adipate, alginates, aspartate, benzoate, benzene sulfonate, disulfate, butyrate, citrate, camphor
Hydrochlorate, camsilate, cipionate, digluconate, lauryl sulfate, esilate, fumarate, Portugal heptan
Sugar lime, glycerophosphate, Hemisulphate, enanthate, caproate, hydrogen chlorate, hydrobromate, hydriodate, 2- hydroxyl second
Sulfonate, lactate, maleate, mesylate, 2- naphthalene sulfonate, nicotinate, nitrate, oxalates, pamoate, pectin ester
Hydrochlorate, persulfate, 3- phenylpropionic acid salt, picrate, Pivalate, propionate, succinate, sulfate, tartrate,
Rhodanate, toluene fulfonate and undecylate.Alkali salt includes ammonium salt, alkali metal salt, such as sodium and sylvite, alkali salt,
Such as calcium and magnesium salts, the salt of organic base, such as dicyclohexyl amine salt, the salt of N- methyl-D-glucamine salt and amino acid, such as essence
Propylhomoserin, lysine etc., moreover, Basic nitrogen-containing groups can be quaternized with such reagent, such as elementary alkyl halide, such as first
The chlorine of base, ethyl, propyl and butyl, bromine and iodide；Dialkyl sulfate, such as dimethyl suflfate, diethylester, dibutyl ester and two
Pentyl ester；The chlorine of long chain halide, such as decyl, lauryl, myristyl and stearyl, bromine and iodide；Aralkyl halide,
The bromide of such as benzyl and phenethyl.It is preferred for generating the acid of acid-addition salts including hydrochloric acid and acetic acid.
The present invention also provides the preparation method of above-mentioned compound of Formula I, this method sees below formula.
Present system is studied and illustrates the structure and preparation of the compound, and the compound is as a new class of
VEGFR-2 tyrosine kinase inhibitor, structure type are novel, provide completely new direction and wide for exploitation new type antineoplastic medicine
Wealthy platform.
Specific embodiment
Embodiment 1
The system of 5- (4- chlorphenyl) -7- (4- methoxyphenyl) -3- methyl -5H- thiazole simultaneously [3,2-a] pyrimidine -2- formic acid
It is standby
0.1 mol of 4- chlorobenzaldehyde, 0.1 mol, 4- methoxyacetophenone of thiocarbamide are added in the round-bottomed flask of 250 mL
0.11 mol, trim,ethylchlorosilane 0.1mol, 30 mL of acetonitrile, stirring, 10 h of back flow reaction.It is cooling, it filters, the anhydrous second of filter cake
Alcohol recrystallization, obtains yellow crystals 4- (4- chlorphenyl) -6- (4- methoxyphenyl) -3,4- dihydro-pyrimidin -2 (1H)-thioketones, receives
Rate 63%.ESI-MS (m/z): 331.2 (M+H)+。
0.05mol4- (4- chlorphenyl) -6- (4- methoxyphenyl) -3,4- dihydro-pyrimidin -2 (1H)-thioketones is added to
In the KOH solution of 10mL10%, 0.05mol4- chloroacetyl acetacetic ester is then added dropwise, after 1h is reacted in heating, ice water dilution has big
It measures crystal to be precipitated, dry 4- [4- (4- chlorphenyl) -6- (4- methoxyphenyl) -1,2,3,4- tetrahydropyrimidine -2- sulphur] -3- oxygen
For ethyl butyrate, yield 48%.
By 0.02mol4- [4- (4- chlorphenyl) -6- (4- methoxyphenyl) -1,2,3,4- tetrahydropyrimidine -2- sulphur] -3- oxygen
It is added in 120 DEG C of 85%PPA for ethyl butyrate, reacts 1h, be cooled to room temperature after reaction, ice water is added, there is a large amount of solids
Be precipitated, filter, dehydrated alcohol be recrystallized to give [5-(4- chlorphenyl) -7- (4- methoxyphenyl) -5H- thiazole is simultaneously [3,2-a] phonetic
Pyridine -3- base]-ethyl acetate, yield 49%.
By 0.01mol [5-(4- chlorphenyl) -7- (4- methoxyphenyl) -5H- thiazole simultaneously [3,2-a] pyrimidin-3-yl]-second
Acetoacetic ester is added in the NaOH of 2mol/L, adds 20mL methanol, is reacted at room temperature 2h, methanol is removed under reduced pressure, with concentrated hydrochloric acid tune
PH=2 have a large amount of solids to be precipitated, and filter, and dehydrated alcohol recrystallizes to obtain buff powder [5- (4- chlorphenyl) -7- (4- methoxyl group
Phenyl) -5H- thiazole simultaneously [3,2-a] pyrimidin-3-yl]-acetic acid, yield 57%, ESI-MS (m/z): 413.2 (M+H)+。
Embodiment 2
2- [5- (4- chlorphenyl) -7- (4- methoxyphenyl)-N, N- dimethyl -5H- thiazole simultaneously [3,2-a] pyrimidine -3-
Base]-acetamide (L1) preparation
10mmol dimethylamine hydrochloride, 10mmol [5- (4- chlorphenyl) -7- (4- methoxyphenyl) -5H- thiazole simultaneously [3,
2-a] pyrimidin-3-yl]-acetic acid, 20mL methylene chloride is added in round-bottomed flask, 12mmolEDCI is then added,
12mmolHOBt and triethylamine 10mmol, after reacting at room temperature 12h, reaction solution successively uses 5%HCl, 5%NaHCO3, it is molten to be saturated NaCl
Liquid is washed, and column chromatography for separation obtains white solid, yield 40% after drying.
1H-NMR (300MHz, DMSO), δ (ppm): 7.47 (2H, d, J=8.7Hz), 7.38 (2H, d, J=
8.4Hz), 7.22 (2H, d, J=8.7Hz), 6.82 (2H, d, J=8.4Hz), 6.73 (H, d), 6.32 (H, s), 6.21
(H, d), 4.28 (2H, s), 3.82 (3H, s), 3.12 (3H, s), 3.06 (3H, s)；ESI-MS (m/z): 440.1 (M
+H)+。
Embodiment 3
2- [5- (4- chlorphenyl) -7- (4- methoxyphenyl)-N, N- diethyl -5H- thiazole simultaneously [3,2-a] pyrimidine -3-
Base]-acetamide (L2) preparation
Dimethylamine hydrochloride is replaced with diethylamine, synthetic method is referring to embodiment 2, yield 32%.
1H-NMR (300MHz, DMSO), δ (ppm): 7.50 (2H, d, J=8.4Hz), 7.36 (2H, d, J=
8.4Hz), 7.25 (2H, d, J=8.7Hz), 6.80 (2H, d, J=8.4Hz), 6.72 (H, d), 6.32 (H, s), 6.20
(H, d), 4.28 (2H, s), 3.84 (3H, s), 3.48 (2H, m), 3.32 (2H, m), 1.18 (3H, t), 1.08 (3H,
t)；ESI-MS (m/z): 468.1 (M+H)+。
Embodiment 4
5- (4- chlorphenyl) -7- (4- methoxyphenyl) -3- [(1- piperidines -1- carbonyl) ethyl] -5H- thiazole simultaneously [3,2-
A] pyrimidine (L3) preparation
Dimethylamine hydrochloride is replaced with piperidines, synthetic method is referring to embodiment 2, yield 30%.
1H-NMR (300MHz, DMSO), δ (ppm): 7.50 (2H, d,J =8.4Hz), 7.30 (2H, d,J =
8.4Hz), 7.22 (2H, d, J=8.7Hz), 6.80 (2H, d, J=8.4Hz), 6.74 (H, d), 6.32 (H, s), 6.15
(H, d), 4.28 (2H, s), 3.84 (3H, s), 3.48 (2H, m), 3.40 (2H, m), 1.60 (2H, m), 1.55 (2H,
M), 1.44 (2H, m), ESI-MS (m/z): 480.1 (M+H)+。
Embodiment 5
2- [5- (4- chlorphenyl) -7- (4- methoxyphenyl) -5H- thiazole simultaneously -3 base of [3,2-a] pyrimidine] -1- morpholine -4-
The preparation of base-acetyl (L4)
Dimethylamine hydrochloride is replaced with morpholine, synthetic method is referring to embodiment 2, yield 35%.
1H-NMR (300MHz, DMSO), δ (ppm): 7.49 (2H, d,J =8.4Hz), 7.28 (2H, d,J =
8.4Hz), 7.14 (2H, d, J=8.4Hz), 6.87 (2H, d, J=8.4Hz), 6.72 (H, d), 6.32 (H, s), 6.12
(H, d), 4.28 (2H, s), 3.84 (3H, s), 3.74 (4H, br), 3.68 (4H, br)；ESI-MS (m/z): 481.1 (M+
H)+。
Embodiment 6
5- (4- chlorphenyl) -7- (4- methoxyphenyl) -3- [(1- (4- methyl piperazine) -1- carbonyl) ethyl] -5H- thiazole
And the preparation of [3,2-a] pyrimidine (L5)
Dimethylamine hydrochloride is replaced with N methyl piperazine, synthetic method is referring to embodiment 2, yield 33%.
1H-NMR (300MHz, DMSO), δ (ppm): 7.54 (2H, d,J =8.4Hz), 7.30 (2H, d,J =
8.4Hz), 7.12 (2H, d, J=8.4Hz), 6.68 (2H, d, J=8.4Hz), 6.71 (H, d), 6.32 (H, s), 6.02
(H, d), 4.28 (2H, s), 3.83 (3H, s), 3.64 (4H, t), 2.46 (4H, t), 2.39 (3H, d)；ESI-MS (m/
Z): 495.2 (M+H)+。
Embodiment 7
- 5H- thiazole is simultaneously by 5- (4- chlorphenyl) -7- (4- methoxyphenyl) -3- [(1- pyrrolidinyl -1- carbonyl) ethyl]
The preparation of [3,2-a] pyrimidine (L6)
Dimethylamine hydrochloride is replaced with nafoxidine, synthetic method is referring to embodiment 2, yield 31%.
1H-NMR (300MHz, DMSO), δ (ppm): 7.52 (2H, d,J =8.4Hz), 7.34 (2H, d,J =
8.4Hz), 7.10 (2H, d, J=8.4Hz), 6.84 (2H, d, J=8.4Hz), 6.71 (H, d), 6.32 (H, s), 6.04
(H, d), 4.26 (2H, s), 3.82 (3H, s), 3.48 (4H, m), 1.87 (4H, m)；ESI-MS (m/z): 466.1(M+
H)+。
Embodiment 8
2- [5- (4- chlorphenyl) -7- (4- methoxyphenyl)-N, N- di-n-butyl -5H- thiazole simultaneously [3,2-a] pyrimidine -3-
Base]-acetamide (L7) preparation
Dimethylamine hydrochloride is replaced with di-n-butyl, synthetic method is referring to embodiment 2, yield 52%.
1H-NMR (300MHz, DMSO), δ (ppm): 7.52 (2H, d, J=9.0Hz), 7.28 (2H, d, J=
9.0Hz), 7.16 (2H, d, J=9.0Hz), 6.69 (2H, d, J=9.0Hz), 6.68 (H, d), 6.32 (H, s), 6.02
(H, d), 3.83 (3H, s), 3.40 (4H, m), 1.61 (4H, m), 1.30 (4H, m), 0.96 (6H, m)；ESI-MS (m/
Z): 524.1 (M+H)+。
Embodiment 9
5- (4- chlorphenyl) -7- (4- methoxyphenyl) -3- [1- (4- (4- bromophenyl) piperazine) -1- carbonyl) ethyl] -
The preparation of 5H- thiazole simultaneously [3,2-a] pyrimidine (L8)
Dimethylamine hydrochloride 1- (4- bromophenyl) piperazine is replaced, synthetic method is referring to embodiment 2, yield 35%.
1H-NMR (300MHz, DMSO), δ (ppm): 7.50 (2H, d,J =8.4Hz), 7.40 (2H, d,J =
8.7Hz), 7.16 (2H, d, J=8.4Hz), 7.02 (2H, d,J =8.7Hz), 6.96 (2H, d,J =8.4Hz), 6.86
(2H, d, J=8.4Hz), 6.71 (H, d), 6.32 (H, s), 6.02 (H, d), 3.80 (3H, s), 3.36 (4H, t),
3.22 (4H, t), ESI-MS (m/z): 635.0 (M+H)+。
The test of mtt assay antitumor cytolytic activity
1. the preparation of material:
Reagent: the RPMl640 culture solution containing 10% fetal calf serum, 0.25% tryptic digestive juice, PBS (0.01mol/
L, pH7.4), DMSO (analysis is pure), MTT solution；
Cell strain: human liver cancer cell SMMC-7221 cell strain.
2. method:
(1) inoculating cell: by the SMMC-7221 cell of logarithmic growth phase, with 0.25% trypsin digestion, with containing 10%
1640 culture mediums of tire calf serum are made into individual cells suspension, with every hole 104A cell inoculation is to 96 orifice plates, every pore volume
100mL;
(2) it cultivates cell: culture plate is put into CO2Incubator, at 37 DEG C, 100% relative humidity contains 5%CO2, 95% air
Incubator in cultivate 24 h；
(3) 5 mg/mLMTT solution are prepared: weighing 250 mg MTT, is put into small beaker, add 50 mL PBS solutions, electricity
Magnetic stirring 30min is saved backup with 0.22 μm of miillpore filter degerming in 4 DEG C, is used in l weeks；
(4) it is administered: aseptically, by target compound 10-7The suspension of mol/L is added to 96 with 100 holes μ L/
In well culture plate, every kind of compound sets 3 in parallel, and 3 blank control wells are set on every culture plate.Place CO2Of the same race in incubator
Under the conditions of continue to cultivate；
(5) colour generation: after 24 h of culture, every hole adds 10 μ LMTT solution, in culture 4h, terminates culture, carefully inhales to abandon in hole and train
Supernatant is supported, is inhaled again after suspension cell centrifugation and abandons culture supernatant in hole.Every hole adds 150 μ LDMSO, vibrates 10min, Shi formazan
Sufficiently dissolution；
(6) colorimetric: 570 nm wavelength of selection measure each hole absorbance value (OD value) on enzyme linked immunological monitor.
Growth of tumour cell inhibiting rate: inhibitory rate of cell growth=(1- experimental group OD value/control is calculated according to following formula
Group OD value) x100%.
3. result: experiment shows that above compound of the invention has inhibiting effect to SMMC-7221 tumour cell, sees
Table 1.
Claims (2)
1. a kind of VEGFR-2 tyrosine kinase inhibitor has anti-tumor activity, it is characterised in that: the compound is with logical
5,7- diphenyl -5H- the thiazole of Formulas I simultaneously [3,2-a] pyrimidine -3- acetamide derivative；
Specifically:
5- (4- chlorphenyl) -7- (4- methoxyphenyl) -3- [(1- piperidines -1- carbonyl) ethyl] -5H- thiazole is simultaneously [3,2-a] phonetic
Pyridine；
2- [5- (4- chlorphenyl) -7- (4- methoxyphenyl) -5H- thiazole simultaneously -3 base of [3,2-a] pyrimidine] -1- morpholine -4- base-second
Acyl；
5- (4- chlorphenyl) -7- (4- methoxyphenyl) -3- [(1- pyrrolidinyl -1- carbonyl) ethyl] -5H- thiazole simultaneously [3,2-
A] pyrimidine.
2. the purposes that compound described in claim 1 is used to prepare anti-tumor drug.
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| "Design, Synthesis, and Biological Evaluation of 5H-Thiazolo[3,2-a]pyrimidine-6-carboxylic Acid Ethyl Ester Derivatives as a Novel Series of Acetylcholinesterase Inhibitors";ZHI Hui et al.;《CHEM. RES. CHINESE UNIVERSITIES》;20091231;第25卷(第3期);第332-337页 |
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